Objective(s): To reveal the detailed mechanism underlying the functions of salidroside on the inflammation of intestinal epithelial cells during IBD. Materials and Methods: Quantitative real-time PCR was employed to assess the expression of IL-6, IL-10, and α-defensins 5 and 6. ELISA assay was performed to measure the secretion of IL-6 and IL-10. MTT assay was used to determine the cell viability and proliferation. Western blot was used to assess the phosphorylation of NF-kB, Erk1/2, JNK, P38, JAK2, and STAT3. Results: Salidroside impaired the proliferation of intestinal epithelial cells at high concentrations ( P < 0.05) and down-regulated interleukin-6 (IL-6) production induced by LPS ( P <0.05). Western blot results showed that salidroside repressed the phosphorylation of NF-kB, Erk1/2, JNK, P38, JAK2 and STAT3 ( P <0.05) and attenuated the activation of NF-κB, MAPK, and STAT3 pathways. Moreover, the expressions of α-defensin 5 and 6 were rescued by salidroside after LPS or SAC triggering ( P <0.05). Conclusion: In summary, salidroside suppressed the expression of IL-6 and elevated the expression of defensins in LPS-activated intestinal epithelial cells through NF-κB/MAPK and STAT3 pathways. The mechanism revealed here may be potentially useful for the treatment of IBD with salidroside.